The central theme of this Program Project revolves around the genetic toxicology of DNA adducts. The chemistry and biology of environmental mutagens, including aromatic amines, benzo(a)pyrenes, food mutagens, estrogen mimics and products of oxidative DNA damage are being investigated. Novel biological systems are employed that reflect the mutagenic specificity of a single DNA adduct and reveal fundamental relationships between structure and biological activity. This information enables mechanisms of mutagenesis and DNA repair to be elucidated at the molecular and cellular level. The focus of this Program on environmental mutagenesis is unchanged. Projects include 1. Synthesis and structure of oligodeoxynucleotides with defined DNA damage; 2. Mutagenic hotspots and the 3D structure of damaged DNA; 3, Mitochondrial DNA damage and repair; 4. PCNA, DNA polymerase delta and DNA damage. A primary objective of Project 1 is to develop methods for the synthesis of oligonucleotides modified site specifically with DNA adducts; these are used for biological research and structural studies. Project 2 proposes to analyze the nature of mutagenic hotspots, to establish the mutagenic potential of bisphenol A, and to establish the mutagenic potential of bisphenol A, and to determine the three dimensional structures of duplex DNA containing DNA adducts. In Project 3, selective aspects of the biochemistry of oxidative DNA damage, including its repair, will be studied in mitochondria. The goals of Project 4 are to study biological effects of mutations in human PCNA. The scientific core component consists of experienced technical staff who prepare chemically-modified oligonucleotides for program participants and perform mass spectral method analysis.